Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit

The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval

How cigarette smoking may increase the risk of anxiety symptoms and anxiety disorders : a critical review of biological pathways

Multiple studies have demonstrated an association between cigarette smoking and increased anxiety symptoms or disorders, with early life exposures potentially predisposing to enhanced anxiety responses in later life. Explanatory models support a potential role for neurotransmitter systems, inflammation, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophins and neurogenesis, and epigenetic effects, in anxiety pathogenesis. All of these pathways are affected by exposure to cigarette smoke components, including nicotine and free radicals. This review critically examines and summarizes the literature exploring the role of these systems in increased anxiety and how exposure to cigarette smoke may contribute to this pathology at a biological level. Further, this review explores the effects of cigarette smoke on normal neurodevelopment and anxiety control, suggesting how exposure in early life (prenatal, infancy, and adolescence) may predispose to higher anxiety in later life. A large heterogenous literature was reviewed that detailed the association between cigarette smoking and anxiety symptoms and disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress, mitochondrial function, neurotransmitter systems, neurotrophins and neurogenesis. Some preliminary data were found for potential epigenetic effects. The literature provides some support for a potential interaction between cigarette smoking, anxiety symptoms and disorders, and the above pathways; however, limitations exist particularly in delineating causative effects. The literature also provides insight into potential effects of cigarette smoke, in particular nicotine, on neurodevelopment. The potential treatment implications of these findings are discussed in regards to future therapeutic targets for anxiety. The aforementioned pathways may help mediate increased anxiety seen in people who smoke. Further research into the specific actions of nicotine and other cigarette components on these pathways, and how these pathways interact, may provide insights that lead to new treatment for anxiety and a greater understanding of anxiety pathogenesis

From quanta forms to brain awarenss

Ewolucja wszechświata od pierwszych cząstek aż do człowieka – istoty świadomej – wskazuje na transdukcyjne możliwości materialnych molekuł. Pochodzące z Wielkiego Wybuchu cząstki odpowiednio skonfigurowane generują efekty nowej natury: świadomość, umysł i jaźń. Źródłem tego procesu jest ludzki mózg. Neurobiologicznym podłożem tych fenomenów są wzorce synaptyczne powstałe dzięki komunikacji neuronalnej. Można wskazać struktury, których aktywność znamionuje działanie psychicznych fenomenów, nie można jednak ich z nimi utożsamić. Nie znamy przyczyny transdukcyjnych zdolności ludzkiego mózgu. Z ewolucyjnego punktu widzenia możliwości materii są ciągle odkrywane. Człowiek i jego mózg są kluczem do tej tajemnicy.The evolution of the universe from the first particles to human – being conscious indicates the possibility of material transduction molecules. Derived from the Big Bang, particles are suitably configured generate new nature effects: consciousness, mind and self. The source of this process is the human brain. Neurobiological substrate of these phenomena are caused due to patterns of synaptic neuronal communication. You can specify the structure, whose activity marks the effects of mental phenomena, but they can not identify with them. We do not know the cause transduction capacity of the human brain. From an evolutionary point of view of the matter they are constantly being discovered. A man and his brain are the key to this mystery

Inviscid Shock Propagation within a Variable-Geometry Scramjet Inlet

The study concerns the propagation of shockwaves within an inlet of a scramjet engine and effect of inlet geometry variation on performance. A Python code was developed to simulate and visualize a flowfield within a scramjet inlet, based on inviscid oblique shock theory. The program was validated against NASA Shock software, and the results differed only by round-off error (0.05%). Subsequently a geometric sensitivity study was conducted, showing that throughout acceleration from Mach 5 to Mach 20 parameters like inlet height could be varied to ensure constant number of shocks within an inlet (preventing discontinuous changes of flowfield), whereas lower wedge angle could control compression required for optimal combustion. Correspondingly, a trajectory was determined with a constraint on static pressure entering combustion chamber (100 kPa). For an arbitrary baseline inlet geometry, it was established that beyond Mach 10 the scramjet would exceed structural load limit, despite delivering sufficient conditions for rapid combustion. Nevertheless, below Mach 10 it would operate efficiently, proving that hydrocarbon-fueled scramjets can have a fixed geometry. For higher speeds, a variable geometry is a necessity

No Specific Subcellular Localization of Protein Kinase C Is Required for Cytotoxic T Cell Granule Exocytosis*

Cytotoxic T cells kill virus-infected cells and tumor cells by releasing lytic granules that contain cell-killing contents. Exocytosis requires calcium influx and protein kinase C (PKC) activation. Here, we extend our previous finding regarding the lack of isoform specificity of PKCs in the granule release step, showing that mutant constitutively active PKCδ can substitute for phorbol esters and support exocytosis. PKCδ, a novel PKC isoform, was recently shown to play a role in lytic granule reorientation. Surprisingly, however, our results suggested that mutant PKCδ did not localize to the plasma membrane (PM). To test directly whether PKC has to be in the PM to drive exocytosis, we generated mutants of various PKC isoforms that were tethered either to the outer mitochondrial membrane or to the PM. Tethered mutant PKCδs were able to promote exocytosis as effectively as the untethered version. The substrates of PKCs involved in lytic granule exocytosis are currently unknown, but subcellular localization is believed to be a critical factor in determining PKC accessibility to substrates. That there is no requirement for specific PKC localization in lytic granule exocytosis may have important implications for the identity of PKC substrates

Interplay of T-cell receptor and interleukin-2 signalling in Vγ2Vδ2 T-cell cytotoxicity

Human peripheral blood Vγ2Vδ2 T cells are important for host defence and tumour immunity. Their unusual T-cell receptor (TCR) recognizes small molecule phosphoantigens; stimulated cells produce inflammatory cytokines and are potently cytotoxic for a variety of tumours. However, molecular mechanisms linking phosphoantigen stimulation and cytotoxicity are incompletely understood. We know that isopentenyl pyrophosphate (IPP) activates mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/Erk) and phosphoinositide 3-kinase (PI-3K)/Akt pathways; specific inhibition of Erk or Akt significantly impairs the functional response to IPP. We now show that interleukin-2 also activates MEK/Erk and PI-3K/Akt pathways but on its own, fails to induce cytokine expression or cytotoxicity. Hence, MEK/Erk and PI-3K/Akt activation are necessary but not sufficient to induce effector responses in Vγ2Vδ2 T cells and a TCR-dependent signal is still required for tumour cell killing. Cyclosporin A, an inhibitor of calcineurin, blocked calcium-dependent nuclear translocation of nuclear factor of activated T cell (NFAT) and significantly reduced IPP-induced cytokine production, degranulation and cytotoxicity. The IPP-induced calcium mobilization and NFAT translocation were necessary to activate Vγ2Vδ2 effector functions; interleukin-2, acting on the MEK/Erk pathway, regulated the strength of these responses. The TCR has a specific role in Vγ2Vδ2 T-cell killing of tumour cells, which is distinct from its role in triggering cellular proliferation in response to phosphoantigens